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Probiotics and Cancer

Introduction:

According to the World Health Organization, probiotics are “live microorganisms, which when administered in adequate amounts confer a health benefit on the host” (FAO 2001). In recent years, researchers have begun to explore the potential applications of probiotics, especially of the genera Lactobacillus and Bifidobacterium, in cancer prevention and treatment. Probiotic cancer treatments are especially appealing because they offer a cheaper, less toxic alternative to standard radiation and chemical based therapies. However, it is difficult to measure the efficiency of probiotics on human subjects in a clinical setting, because probiotics must often be taken before the onset of clinical disease. Thus, most studies in this area have been done in animal models or in in vitro settings. Thus, their replicability in humans remains uncertain, due in part to the complex, dynamic and largely uncharacterised nature of the human microbiome. Furthermore, the wide variety of bacterial candidates available for probiotic treatments means that there is a large variation in the processes by which they can carry out their anti-cancer functions (see Figure 1).

The Normal Flora:

The human normal flora is the set of microorganisms that inhabit the various non-sterile regions of the body including the gastrointestinal, respiratory and urogenital tracts, the oral cavity, and the skin (Davis 1996). It is established during movement through the birth canal as well as for the days and weeks that follow, and is derived from the environment into which the infant is born (Davis 1996). The normal flora is highly variable, and its composition can be significantly altered between individuals due to factors such as age, diet, health, and geographic location (McFarland 2000). It can also vary within an individual over time due to factors such as stress, illness, antibiotic exposure, hormonal changes and probiotic consumption (McFarland 2000). The functions of the normal flora are essential to human life, and include such things as vitamin production, assistance with digestion, maturation and recycling of intestinal epithelial cells, and production of exogenous enzymes (McFarland 2000). The normal flora is also essential for immune system development, and can further protect the body by preventing attachment of bacterial pathogens and by synthesizing antimicrobial peptides (McFarland 2000). However, the normal flora can also harbour opportunistic pathogens such as Staphylococcus aureus that cause disease in immunocompromised individuals (Davis 1996).

Removal of Carcinogens:

Several of the most well characterised methods of probiotic anti-cancer activity are related to the ability of organisms to directly disrupt the effect of carcinogens on the cells of the body. Bacterial species are able to do this in a variety of ways, including by removing carcinogens from the intestinal lumen. For example, heterocyclic aromatic amines (a class of carcinogens produced from overcooked meat that include Trp-P-1/2 and IQ) can be bound and inactivated on the surface of Bifidobacterium longum and other lactic acid bacteria (Orrhage et al 1994.). Rhee and Park (2001) found that the bacterium Lactobacillus plantarum was able to secrete three different glycoproteins that are antimutagenic against MNNG, a common food carcinogen. This researched supplemented research already completed that identified a variety of antimutagenic properties belonging to Lactobacillus sp., including an anti-tumour component of the Lactobacillus bulgaricus cell wall (Bogdanov et al. 1977).

Bacterial Enzyme Inhibition

Another activity of probiotic bacteria associated with cancer prevention is the ability of certain organisms to inhibit the activity of bacterial enzymes that form carcinogens as products. For example, B. longum was found to inhibit the activity of beta-glucuronidase, which is responsible for cleavage of complex carbohydrates and has been implicated in the origin of colon cancer through a largely unknown mechanism that yields carcinogenic products from procarcinogenic compounds found in food (Kulkarni and Reddy 1994 ). This decreased activity was correlated with an observed decrease in the number and severity of colon tumours, as well as the inhibition of induced tumourigenesis caused by the carcinogen azoxymethane (Singh et al. 1997). In addition, consumption of B. longum cultures was associated with a decrease in colon, liver and mammary carcinogenesis caused by the common food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline, commonly known as IQ (Reedy and Rivenson 1993) (see Figure 2).

Production of Anti-Carcinogenic Compounds:

Certain probiotic organisms can produce compounds that themselves play anti-carcinogenic roles in the body, which aid in the suppression of tumourigenesis and tumour growth/proliferation. Strains of both Lactobacillus and Bifidobacterium have been found to convert linoleic acids, a type of essential fatty acids, into conjugated linoleic acids which have widespread anti-cancer properties including the ability to reduce cancer cell viability and induce apoptosis in cancer cells (Kumar et al. 2010). Moreover, certain strains of lactic acid bacteria can work symbiotically with other bacteria of the normal flora by producing short chain fatty acids which are then converted into the anticarcinogenic fatty acid butyrate (Commane et al. 2005).

Immunomodulation:

One of the more systematic mechanisms whereby probiotic bacteria are thought to help prevent and/or counteract tumour formation and growth is via immunomodulation. An excellent example of immunomodulation by probiotics is the Shirota strain of Lactobacillus casei (LcS). This bacterial strain, chosen for its biological activity in humans, is capable of upregulating the cytotoxic ability of natural killer cells (Takeda and Okamura 2007) (see Figure 3), which are known to be essential in the detection and elimination of tumour cells in vivo via a cytotoxic killing mechanism (Herberman and Ortaldo 1981). Matsuzaki (1998) found that this bacterial strain is also capable of stimulating the release of inflammatory cytokines such as INF-γ and TNF-α as well as proliferative cytokines such as IL-2 which are responsible for a host of downstream immune responses. They correlated this cytokine release with increased macrophage and T cell activations that are responsible for the significant anti-tumour and anti-metastatic response observed in murine models after intrapleural treatments with LcS. However, a polysaccharide component of LcS cell wall has also been shown have anti-inflammatory effects,such as the downregulation of IL-6, that can provide protection from cancers of the colon (Matsumoto et al. 2009). Thus, the immunomodulatory effects of probiotics such as LcS can be varied, including both pro- and anti-inflammatory responses.

Induction of Apoptosis:

Another mechanism by which probiotics can prevent and suppress tumour formation is by causing selective apoptosis of tumour cells. For example, B. longum has been shown to cause DNA fragmentation and apoptosis of the adenocarcinoma cell line Caco-2 (Lorenzo 2005). Another probiotic species, Lactobacillus reuteri, has been shown to cause apoptosis of myeloid leukemia-derived cells in vitro by inhibiting the activation of the transcription factor NF-κB, which is responsible for cell proliferation and survival, as well as upregulating the pro-apoptotic MAPK protein kinases (Iyer et al. 2008). However, little is known about the mechanisms underlying these processes, and no in vivo studies have been published to date.

Works Cited:

Bogdanov, I. G., Velichkov, V.T., Gurevich, A.I., Dalev, P.G., and Kolosov, M.N. 1977. Antitumor effect of glycopeptides from the cell wall of Lactobacillus bulgaricus. Bulletin of Experimental Biology and Medicine, 84 (12):709-12.

Commane, D., Hughes, R., Shortt, C., and Rowland, I. 2005. The potential mechanisms involved in the anti-carcinogenic action of probiotics. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 591 (1-2): 276-289.

Davis, C.P. 1996. Normal Flora, pg. 1011-1026. In Baron, S. (ed.), Medical Microbiology, 4th ed. University of Texas Medical Branch at Galveston, Galveston, Texas

Food and Agriculture Organization of the United Nations (FAO). 2001. Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria, http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf

Herberman, R.B. and Ortaldo, J.R. 1981. Natural killer cells: their roles in defenses against disease. Science, 214 (451): 24-30.

Iyer, C., Kosters, A., Sethi, G., Kunnumakkara, A.B., Aggarwal, B.B., and Versalovic, J. 2008. Probiotic Lactobacillus reuteri promotes TNF-induced apoptosis in human myeloid leukemia-derived cells by modulation of NF-κB and MAPK signalling. Cellular Microbiology, 10 (7): 1442-1452.

Kulkarni, N and Reddy, B.S. 1994. Inhibitory effect of Bifidobacterium longum cultures on the azoxymethane-induced aberrant crypt foci formation and fecal bacterial beta-glucuronidase. Proceedings for the Society of Experimental Biology and Medecine. 207 (3):278-83

Kumar, M., Kumar, A., Nagpal, R., Dheeraj, M., Bahare, P., Verma, V., Kumar, P., Poddar, D., Aggarwal, P.K., Henry, C.J.K., Jain, S., and Yadav, H. 2010. Cancer-preventing attributes of probiotics: an update. International Journal of Food Sciences and Nutrition, 61 (5): 473–496.

Lorenzo, N. 2005. Study of apoptotic deletion mediated by Bifidobacterium longum with construction of recombinant strains for Serpin encoding gene and phenotypes comparison in a pig cell model. Ph. D. Agricultural Microbiology Thesis, Maribor University, Maribor, Slovenia.

Matsumoto, S,. Hara, T., Nagaoka, M., Mike, A., Mitsuyama, K., Sako, T., Yamamoto, M., Kado, S., and Takada, T. 2009. A component of polysaccharide peptidoglycan complex on Lactobacillus induced an improvement of murine model of inflammatory bowel disease and colitis-associated cancer. Immunology, 128 (1): 170-180.

Matsuzak, T. 1998. Immunomodulation by treatment with Lactobacillus casei strain Shirota. International Journal of Food Microbiology. 41 (2): 133–140.

McFarland, L.V. 2000. Normal flora: diversity and functions. Microbial Ecology in Health and Disease, 12: 1193-207.

Orrhage, K., Sillerströma, E., Gustafsson, J.A., Norda, C.E., and Rafter, J.1994. Binding of mutagenic heterocyclic amines by intestinal and lactic acid bacteria. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 311(2): 239-248.

Rafter, J. 2003. Probiotics and Colon Cancer. Best Practices and Research Clinical Gastroenterology, 17 (5): 849-859.

Reddy, B.S. and Rivenson, A. 1993. Inhibitory Effect of Bifidobacterium longum on Colon, Mammary, and Liver Carcinogenesis Induced by 2-Amino-3-methylimidazo[4,5-f]quinoline, a Food Mutagen. Cancer Research, 53: 3914-3918.

Rhee, C. and Park, H. 2001. Three Glycoproteins with Antimutagenic Activity Identified in Lactobacillus plantarum KLAB21. Applied Environmental Microbiology, 67 (8): 3445–3449.

Singh, J., Rivenson, A., Tomita, M., Shimamura, S., Ishibashi, N., and Reddy, B.S. 1997. Bifidobacterium longum, a lactic acid-producing intestinal bacterium inhibits colon cancer and modulates the intermediate biomarkers of colon carcinogenesis. Carcinogenesis, 18 (4): 833–841.

Takeda, K. and Okumura, K. 2007. Effects of a Fermented Milk Drink Containing Lactobacillus casei Strain Shirota on the Human NK-Cell Activity. The Journal of Nutrition, 137 (3): 791-793.